Spontaneous Remission and Clonal Relapse in Congenital Infant Leukemia: Single-Cell Atlas Profiling and Curative Transplantation

Congenital leukemia is an exceptionally rare malignancy with an incidence below five per million births and poor prognosis, especially in cases with KMT2A rearrangements. Spontaneous remission (SR) is an uncommon phenomenon; since 1996, only five SR cases with KMT2A rearrangements have been reported worldwide. We describe a neonate with congenital AML-M5 carrying a KMT2A-MLLT3 fusion, who achieved SR without chemotherapy but relapsed at 5 months with extensive extramedullary disease. At relapse, we performed the world’s first single-cell transcriptomic sequencing of SR-associated congenital leukemia. Analysis showed no proliferative advantage in leukemic progenitors but marked autophagy upregulation and an incomplete immune evasion phenotype, suggesting transient dormancy and partial susceptibility to cytotoxic T-cell surveillance. The patient subsequently achieved molecular remission with CCLG-AML-2024 chemotherapy and remained disease-free following matched unrelated HSCT at 12 months. This case highlights the fragile balance between leukemic clones and host immunity in early life, suggesting autophagy activation and immune sensitivity as natural restraints on leukemogenesis. It emphasizes that SR represents a temporary pause rather than cure, requiring close molecular monitoring, and provides the first single-cell atlas of SR-type congenital leukemia, offering new directions for immunomodulatory and autophagy-targeted therapies in high-risk KMT2A-rearranged leukemia.